Use of 3-substituted oxindole derivatives as kcnq potassium channel modulators

Abstract

The present invention relates to a novel method of treating of pain or anxiety, using compounds that modulate KCNQ potassium channels and currents.

1 . Use of a 3-substituted oxindole derivative having the general Formula I,  
       wherein, 
 R represents hydrogen, halogen or hydroxy.  
 R 1 , R 2 , R 3  and R 4  independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl, or  
 R 1  and R 2 , R 2  and R 3 , or R 3  and R 4  are joined together to form a benzo fused ring,  
 R 5  represents hydrogen or alkyl, and  
 R 6  represents halogen or trihalogenmethyl,  
 or a pharmaceutically-acceptable addition salt thereof,  
 wherein said oxindole derivative is capable of modulating the ion flow through KCNQ channels, 
 for the manufacture of a pharmaceutical composition,  
 for the treatment, prevention or alleviation of a disease or a disorder or a condition of a living animal body selected from the group consisting of pain, neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, to postherpetic neuralgia and to peripheral nerve injury, drug addiction, affective disorders, Alzheimer's disease, anxiety, CNS damage caused by neurodegenerative illness or diseases, cognitive deficits, compulsive behaviour, dementia, HIV dementia, depression, Huntington's disease, mania, cognitive disorders, memory impairment, memory disorders, memory dysfunction, motion disorders, motor disorders, neurodegenerative diseases, Parkinson's disease, Parkinson-like motor disorders, phobias, Pick's disease, psychosis, a bipolar disorder, schizophrenia, spinal cord damage, cardiomyopathia, cardiac arrhythmia, long QT syndrome, a motion disorder, or a motor disorder, myasthenia gravis, migraine, tension headache, a bowel disorder, an inflammatory disease, ulcerative colitis, Crohn's disease, Creutzfeid-Jacobs disease, an ophthalmic condition, progressive hearing loss or tinnitus, fever, multiple sclerosis, diabetes, or metastatic tumor growth, a pneumoconiosis, such as aluminosis, anthracosis, asbestosis, chalicosis, ptilosis, siderosis, silicosis, tabacosis and byssinosis; and a chronic obstructive pulmonary disease (COPD).  
 
 
     
     
         2 . Use according to  claim 1 , wherein the said disease, disorder or condition is selected from the group consisting of pain, neuropathic pain, chronic headache, central pain, pain related to diabetic neuropathy, to postherpetic neuralgia and to peripheral nerve injury.  
     
     
         3 . Use according to  claim 1 , wherein 
 R represents hydrogen, halogen or hydroxy,    R 1 , R 2 , R 3  and R 4  independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl, and when R 1  and R 4  are hydrogen, then R 2  or R 3  is phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl; or    R 1  and R 2 , R 2  and R 3 , or R 3  and R 4  are joined together to form a benzo fused ring,    R 5  represents hydrogen or alkyl, and    R 6  represents halogen or trihalogenmethyl.    
     
     
         4 . Use according to  claim 1 , wherein 
 R 1 , R 3  and R 4  represent hydrogen, and    R 2  represents halogen, trihalogenmethyl or phenyl.    
     
     
         5 . Use according to  claim 1 , wherein 
 R 1  and R 2 , R 2  and R 3 , or R 3  and R 4  are joined together to form a benzo fused ring.    
     
     
         6 . Use according to any of claims  1 - 4 , wherein 
 R 5  is hydrogen or methyl.    
     
     
         7 . Use according to any of claims  1 - 5 , wherein 
 R 6  is chlorine.    
     
     
         8 . Use according to  claim 1 , wherein 3-substituted oxindole derivative for use according to the invention is 
 (+)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;    (−)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6-(trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-6(4-methylphenyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-indol-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-4,6-dichloro-1,3-dihydro-2H-indol-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-6-phenyl-2H-indol-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-6-iodo-2H-indol-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-6-trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-6-[4-(trifluoromethyl)-phenyl]-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[e]indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benz[f]indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-2H-benx[g]indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-4-(trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;    (−)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-hydroxy-6-(trifluoromethyl)-2H-indol- -2 -one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-7-(trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-5-bromo-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-6-iodo-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-4,6-dichloro-1,3-dihydro-3-hydroxy-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[f]indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4,6-bis-(trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-4-(trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;    (+)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;    (−)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-(trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-7-(trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-4,6-dichloro-1,3-dihydro-3-hydroxy-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-5-bromo-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-6-iodo-2H-indol-2-one;    (±)-1,3-dihydro-3-hydroxy-3-[2-hydroxy-5-(trifluoromethyl)-phenyl]-6-(trifluoromethyl)-2H-indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[g]indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-hydroxy-2H-benz[f]indol-2-one;    (±)-3-(5-chloro-2-hydroxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one;    (3S)-(+)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol-2-one;    (3R)-(−)-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-(trifluoromethyl)-2H-indol2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-7-(trifluoromethyl)2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-phenyl-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-6-iodo-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-5-methyl-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-5-bromo-2H-indol-2-one;    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-4,6-bis-(trifluoromethyl)-2H-indol-2-one; or    (±)-3-(5-chloro-2-methoxyphenyl)-1,3-dihydro-3-fluoro-7-(trifluoromethyl)-2H-indol-2-one;    or a pharmaceutically-acceptable addition salt thereof.    
     
     
         9 . A pharmaceutical composition comprising a therapeutically-effective amount of a 3-substituted oxindole derivative having the general Formula I,  
       wherein, 
 R represents hydrogen, halogen or hydroxy,  
 R 1 , R 2 , R 3  and R 4  independently of each another represent hydrogen, halogen, alkyl, trihalogenmethyl, phenyl, p-methyl-phenyl or p-trihalogenmethyl-phenyl, or  
 R 1  and R 2 , R 2  and R 3 , or R 3  and R 4  are joined together to form a bezo fused ring,  
 R 5  represents hydrogen or alkyl, and  
 R 6  represents halogen or trihalogenmethyl,  
 or a pharmaceutically-acceptable addition salt thereof, together with at least one pharmaceutically-acceptable carrier or diluent,  
 wherein said oxindole derivative is capable of modulating the ion flow through KCNQ channels and incapable of modulating the ion flow through BK channels, for the treatment, prevention or alleviation of a disease or a disorder or a condition that is responsive to modulation of KCNQ channels.